Let $M$ be a complete connected Riemannian manifold. Choose a point $p\in M$ and an orthonormal frame $E=(e_1,\cdots,e_n)\subset T_pM$. Given an isometry $g\in\operatorname{Iso}(M)$, we can act on $E$ with $g$ to obtain a new frame $gE=(dg(e_1),\cdots,dg(e_n))\subset T_{g(p)}M$. Further, if $g_1E=g_2E$ then $g_1=g_2$ (since the exponential map is surjective and commutes with isometries). Thus, the map $g\mapsto gE$ is injective, and $\operatorname{Iso}(M)$ can be realized as a subset of the bundle of orthonormal frames $OFM$.
The largest possible isometry group is one for which the map $g\mapsto gE$ is surjective, i.e. one which acts transitively on orthonormal frames. This is the case for $O(n+1)$ on the sphere.